tbuckley/cabot-search huggingface dataset:
A randomized study to measure and enhance the health-related quality of life in patients with cancer receiving immune checkpoint modulators (ME-Q).
Authors: Marcos Aurelio Fonseca Magalhaes Filho, PEI JYE VOON, Lindsay Carlsson, Grace Silver, Aaron Richard Hansen
Journal: Journal of Clinical Oncology (2022)

TPS6603 Background: Existing data demonstrate the impact of Immune checkpoint modulators (ICMs) on Health-Related Quality of Life (HRQOL), but this was from studies that used HRQOL tools developed for patients treated with chemotherapy and/or radiation. To address this gap, we developed a toxicity subscale to cover important immune-related adverse events (irAEs) to combine this subscale with the generic FACT-G to measure HRQOL in patients treated with ICMs, the FACT-ICM. This trial proposes to validate the use of the FACT-ICM as a tool for HRQOL measurement and simultaneously to assess the benefit of remote symptom monitoring and management using a new electronic platform developed specifically for patients receiving ICMs. Methods: Participants will be randomized (1:1) before starting their standard of care ICM therapy to either usual care or the monitoring arm. The ME-Q platform uses a web-based application to enable remote monitoring of patient symptoms and HRQOL, allowing all participants enrolled in both the usual care or monitoring arms to complete the FACT-ICM and other questionnaires (DART, Health Resource Utilization, Decision regret scale, post-study system usability questionnaire) at set time points. Patients on the monitoring arm will have their electronic responses sent automatically, and new or significant worsening symptoms of clinical concern will generate an alert to the advanced practicing nurse (APN) responsible for replying to the patient and acting on responses. Via phone or a video teleconference, the nurse will perform a targeted assessment and provide standardized clinical advice and interventions based on well-established clinical algorithms and international guidelines for the management of irAEs. The APN will inform the patient's clinical team about the patient's responses and obtain the treating team's input and agreement on a proposed treatment plan. Patients enrolled in the usual care arm will respond to the questionnaires; however, their responses are not transmitted to their clinical team. The primary objective will be to validate the PRO tool for HRQOL measurement, and the secondary objective is to improve HRQOL in cancer patients receiving ICMs by remote monitoring and symptom management using the ME-Q electronic platform. We estimate that a total sample size of 266 patients (divided into two arms) achieves 90% power to detect an effect size of 0.4 in mean score changes (from baseline to 4 months) between arms using a two-sample t-test with a two-sided significance level of 0.05. Enrolment is to be completed in 2 years.
OTHR-38. The development of patient-derived models of pediatric brain tumors
Authors: Julie Messiaen, Marleen Derweduwe, Annelies Claeys, Lien Solie, Raf Sciot, Isabelle Vanden Bempt, Steven Devleeschouwer, Frank Van Calenbergh, Philippe De Vloo, Bart Depreitere, Sandra Jacobs, Frederik De Smet
Journal: Neuro-Oncology (2022)

Abstract Brain tumors are still a major cause of morbidity and mortality in children, despite extensive research. An individualized therapy is warranted to combat the heterogeneity present in these tumors. Therefore, this study aims at developing patient-derived models from both low- and high-grade tumors. As such, the heterogeneity in these tumors can be further characterized and treatment sensitivities can be studied. All pediatric patients diagnosed with a brain tumor at the University Hospitals Leuven and receiving surgical intervention were included after informed consent. If sufficient tumoral material was available, a fresh tumor sample was collected during surgery. The sample was processed into dissociated cells, which were grown in culture in order to develop a patient-derived cell line (PDCL). Biomarker expression using a qPCR array was performed if growth beyond passage 3 was achieved. Established PDCLs were subsequently subjected to genomic and transcriptional profiling and cytotoxicity assays were performed to determine therapeutic sensitivities. Patient-derived xenografts (PDX) are developped in selected cases. 70 patients were included prospectively up until January 2022 and tumoral material was available for 50 of them. In total, 10 PDCLs could be generated (3 high-grade, 7 low-grade tumors), while 9 early cultures (3 high-grade, 6 low-grade) are still being expanded. qPCR and sequencing analysis confirm preservation of driving mutations. The high level of growth failures of the PDCLs can be explained by the high proportion of lower grade tumors included. One PDX model was generated. In conclusion, novel patient-derived models from pediatric brain tumors have been generated, which recapitulate the characteristics of the original tumor. The models are a valuable tool to study these tumors and the responses to different treatments. Further on, we will continue with the development of these models and the study of their therapeutic sensitivities. This will help further improving the understanding of these tumors.
Tenascin-C provokes cardiac fibrosis and endothelial impairment in Duchenne Muscular Dystrophy
Authors: P L Szabo, M Inci, K Hilber, D Abraham, S Trojanek, S Costantino, F Paneni, B K Podesser, A Kiss
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): FWF Austrian Science Fund Cardiac fibrosis and dilated cardiomyopathy are major contributors to mortality in Duchenne muscular dystrophy (DMD) patients. There is a growing collection of evidence that Tenascin C (TN-C) plays a maladaptive role in cardiac remodelling and fibrosis. Our aims were to 1) assess the vascular dysfunction and cardiac fibrosis and its link to TN-C in a mouse model of DMD and 2) explore the effect of knocking out TN-C in dystrophic mice. Male wt, mdx and mdx TN-C KO age-matched mice were used. Cardiac fibrosis was assessed on tissue sections. Wire myography was used to test the vascular reactivity and endothelial cells (ECs) were isolated from mouse lung tissues to characterize the oxidative stress and inflammatory marker expression. To study the signalling pathways contributing to cardiac fibrosis, human cardiac fibroblasts (hCFs) were treated with TN-C or TGF-β and gene expression and epigenetic regulation of p65 were assessed. Cardiac fibrosis was markedly increased in mdx mice which was accompanied with elevated TN-C level in cardiac tissue and plasma compared to wt animals. In addition, endothelial cells isolated from mdx mice also showed a marked upregulation of oxidative stress and inflammatory markers and in line with that vascular endothelial function was impaired in mdx mice. Interestingly, mdx- TN-C KO mice showed preserved vascular function as well as reduced cardiac fibrosis compared to age-matched mdx mice. hCFs treated with TN-C or TGF-β showed increased collagen and α-SMA expressions which could be reduced by TN-C siRNA. In addition, both TN-C and TGF-β promote p65/NF-κB promoter demethylation and subsequently stimulate pro-inflammatory and pro-fibrotic signalling, which could be reversed by applying p38 MAPK inhibitor in hCFs. TN-C promotes oxidative stress and inflammation in ECs and fibroblasts, contributing to severe endothelial dysfunction and cardiac fibrosis. In addition, activation of NF-κB p65 signalling pathway may play a role in TN-C induced fibrosis. Thus, TN-C may be a critical mediator and potential target for therapy in DMD.
Impact of antibiotics on stage IV pancreatic ductal adenocarcinoma treated with gemcitabine or 5-fluorouracil.
Authors: Daniel Jeremy Fulop, Haley Zylberberg, Linda Wu, Anne Aronson, Arielle Labiner, Deirdre Jill Cohen, Keith Magnus Sigel, Aimee L. Lucas
Journal: Journal of Clinical Oncology (2022)

e16292 Background: Recent studies have suggested a role for the tumor microbiome in conferring chemoresistance to gemcitabine (GEM) in patients with pancreatic ductal adenocarcinoma (PDAC). One proposed resistance mechanism is the presence of bacterial enzymes that metabolize GEM, but not 5-fluorouracil (5-FU). We therefore assessed the impact of antibiotic receipt in the month before and after initiation of either GEM- or 5-FU-based chemotherapy on PDAC overall survival (OS). Methods: We used the SEER-Medicare database to identify adults &gt;66 years old with stage IV PDAC treated with either first-line GEM or 5-FU between 2007-2017. Antibiotic receipt was defined as a claim for &gt;5 days of oral antibiotics or &gt;1 intravenous antibiotic in the month before or after chemotherapy initiation. Demographic and clinical characteristics were compared using chi-squared and student t-tests, and univariable survival was assessed using Kaplan-Meier methods. Propensity scores (PS) were created to account for potential allocation bias in the receipt of antibiotics. We fit PS-adjusted Cox proportional-hazard models to evaluate the association between antibiotic receipt and OS. Results: We identified 3,990 stage IV PDAC patients treated with first-line GEM-based (n = 3,219) or 5-FU-based (n = 771) chemotherapy, of whom 2,318 (58.1%) received antibiotics. In univariable analyses, antibiotic receipt in the month surrounding chemotherapy initiation was associated with improved median OS in patients treated with GEM (214 days vs 199 days, p = 0.04) but not in patients treated with 5-FU (255 days vs 284 days, P = 0.14). In PS-adjusted multivariable analyses, the significant association between antibiotic receipt and improved OS in patients who received GEM remained (HR 0.89, 95% CI 0.83-0.96). However, no significant association between antibiotic receipt and OS was seen in patients treated with 5-FU (1.10, 95% CI 0.94-1.28). Conclusions: Antibiotic receipt in the month before or after chemotherapy initiation was associated with improved OS in stage IV PDAC patients who received GEM but not 5-FU. These findings support the concept that antibiotics may impact the activity of GEM-metabolizing bacteria proposed to confer chemoresistance. Further studies are needed to characterize the potential role for antibiotics in PDAC treatment.[Table: see text]
Machine learning application to find patients with lower-risk myelodysplastic syndrome from real-world data.
Authors: Colden Johanson, Hu T. Huang, Danny Idryo, Ronda Broome, Matthew J. Rioth, Rayna K. Matsuno
Journal: Journal of Clinical Oncology (2022)

1555 Background: It is a challenge to identify patients with myelodysplastic syndrome (MDS) using structured data from electronic health records (EHRs). Current claims-based algorithms incorporating diagnosis codes, clinical labs, and procedures have not been validated against an expert reference standard. A machine learning-based approach was investigated to identify erythropoietin-stimulating agent (ESA)-treated, lower-risk (LR)-MDS patients from structured EHR data. Methods: A sample of 1,549 patients from the Syapse Learning Health Network (SLHN) was identified as potential ESA-treated LR-MDS patients by a team of clinicians and epidemiologists based on diagnosis and medication data from multiple health systems’ EHRs and cancer registries. Of these, 404 (25%) were confirmed as ESA-treated LR-MDS patients through a review of patient records by certified cancer registrars (CTRs). The sample was divided into training and validation sets at a ratio of 80/20, stratified by the outcome. Age, sex, diagnosis codes corresponding to MDS and chronic kidney disease, medication (ESA, luspatercept, lenalidomide), clinical lab tests (hemoglobin, absolute neutrophils, platelet, blast percentage), and evidence of bone marrow biopsy were included as the predictive variables for the models. Gradient boosting machines with a nested cross-validation scheme were adopted to build the optimal model on the training set. Model acceptance was evaluated based on precision and recall on the validation set. The optimal model was then applied to the remaining unscreened SLHN patient population. Results: The optimal model identified an additional cohort of 157 patients based on the predicted likelihood. Among these, 69 (44%) were CTR-confirmed ESA-treated LR-MDS patients, all of whom were previously missed by the initial expert-determined selection criteria, as shown in the table. Conclusions: The application of machine learning methods increased the rate of ESA-treated MDS patient identification even after the expertly-determined population was depleted. This suggests the application of machine learning models using EHR data may improve the efficiency of MDS patient identification and screening efforts for research, quality improvement, and clinical care. [Table: see text]
Tumor-infiltrating lymphocyte enrichment predicted by CT radiomic analysis is associated with clinical outcomes of immune checkpoint inhibitor in non–small cell lung cancer.
Authors: Changhee Park, Dong Young Jeong, Yeonu Choi, You Jin Oh, Jonghoon Kim, Sergio Pereira, Kyunghyun Paeng, Chan-Young Ock, Se-Hoon Lee, Ho Yun Lee
Journal: Journal of Clinical Oncology (2022)

2663 Background: Enrichment of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment (TME) is a reliable biomarker of immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). Phenotyping through CT radiomics has the overcome the limitations of tissue-based assessment, including for TIL analysis. Here, we objectively assess TIL enrichment using an artificial intelligence-powered H&amp;E analyzer, Lunit SCOPE IO, and analyze its association with advanced quantitative imaging features extracted via radiomic analysis. Clinical significance of the selected radiomic features (RFs) is then validated in independent NSCLC patients who received ICI. Methods: In the training cohort, which included 235 NSCLC patients with both tumor tissue and corresponding CT images obtained within 1 month, we extracted 86 RFs from the CT images. From tissue, a patient’s TIL enrichment score (TILes) was defined as the fraction of tissue area with high intra-tumoral or stromal TIL density, divided by the whole TME area, as measured on an H&amp;E slide. From the corresponding CT images, the least absolute shrinkage and selection operator model was then developed using features that were significantly associated with TIL enrichment. The CT model was then applied to CT images from the validation cohort, which included 242 NSCLC patients who received ICI as ≥ second line. Results: Among the extracted RFs, 22 features were significantly associated with TILes (p &lt; 0.005). After excluding features of multicollinearity and/or zero-coefficient, two features, gray level variance (coefficient 1.71 x 10 -3 ) and low gray level emphasis (coefficient -2.48 x 10 -5 ), were finally included in the model. The two features were both computed from the size-zone matrix (SZM), the idea of which is to break down a given tumor volume into smaller spatially contiguous compartments of different sizes. In the validation cohort, the patients with high predicted TILes (≥ median) had significantly prolonged progression-free survival compared with those with low predicted TILes (median 3.81 months [95% CI 2.14 – 5.69] versus 1.94 months [95% CI 1.58 – 2.93], hazard ratio 0.69 [95% CI 0.53 – 0.90], p = 0.007). Conclusions: This CT radiomics model is able to assess TIL enrichment in TME, which is significantly associated with favorable ICI outcomes in NSCLC. Analyzing the TME through radiomics may overcome limitations of tissue-based analysis and inform clinical decisions, particularly related to use of ICI.
Pyrotinib-based therapy for patients with HER2-positive breast cancer: A multicenter, real-world study.
Authors: Haoqi Wang, Yueping Liu, Hua Yang, Shuaibing Wang, Guozhong Cui, Jie Ma, Yunjiang Liu, Xianqiao Li, Ruizhen Luo, Wei Zhang, Cuizhi Geng
Journal: Journal of Clinical Oncology (2022)

1040 Background: Pyrotinib, an irreversible pan-ErbB inhibitor, has been approved for the treatment of HER2-positive advanced breast cancer in China. Real-world data is instructive for effect evaluation and application of the drug in clinical practice. Herein, this study was conducted to evaluate the effectiveness and safety of pyrotinib-based therapy in patients with HER2-positive breast cancer in the real-world setting. Methods: In this retrospective, multicenter, real-world study, data of patients with HER2-positive breast cancer who received pyrotinib-based therapy from 19 sites were reviewed. Disease characteristics, prior therapies, and treatment patterns were summarized. Progression-free survival (PFS) and the incidence of diarrhea were analyzed. Results: Between September 2018 and June 2021, a total of 378 patients with HER2-positive advanced breast cancer were included. Of 378 patients, 47.4% had hormone receptor (HR)-positive disease, 41.3% had HR-negative disease, and 11.4% had unknown HR status. Brain, lung, liver, and bone metastases were found in 24.9%, 35.7%, 31.7%, and 33.1% of all cases, respectively. Most of patients (83.1%) were trastuzumab-exposed, 12.7% were pertuzumab-exposed, and 8.2% had been treated with lapatinib or neratinib before receiving pyrotinib. Pyrotinib plus chemotherapy (211 [55.8%]) was the most commonly used regimen, followed by pyrotinib monotherapy (115 [30.4%]), pyrotinib plus trastuzumab and chemotherapy (29 [7.7%]), other regimens (18 [4.8%]), and unknown regimen (5 [1.3%]). Standard dose (400 mg once daily) was used in 256 (67.7%) patients. With a median follow-up duration of 20.5 months, the median PFS was 13.0 months (95%CI, 12.0-14.0). Further analyses showed that the median PFS did not differ in subgroups by age (≥65 or &lt; 65 years), HR status (positive or negative), brain metastasis (yes or no), lung metastasis (yes or no), liver metastasis (yes or no), bone metastasis (yes or no), prior exposure to trastuzumab (yes or no), treatment regimen (pyrotinib monotherapy or combination therapy). Significant variance was discovered between sufficient dosage group and non-sufficient group (13.2 months vs 10.93 months, p= 0.028). The survival advantage of sufficient dosage was also evident in brain metastasis cases (14.4 months vs 8.3 months, p= 0.043).The most common adverse event was diarrhea (85.7%), and grade ≥3 diarrhea occurred in 18.5% of patients. Diarrhea was the leading cause for does reduction of pyrotinib. Conclusions: The PFS data in our study was similar to previous clinical trials referring to HER2-positive advanced breast cancer treated with pyrotinib. Cases with brain metastasis also displayed a satisfactory survival result. Sufficient dosage is of great importance for prolonged survival, prevention of diarrhea may efficiently avoid does reduction and guarantee the drug efficacy.
HGG-60. Structural variants shape driver combinations and outcomes in pediatric high-grade glioma
Authors: Frank Dubois, Ofer Shapira, Noah Greenwald, Travis Zack, Jeremiah Wala, Jessica Tsai, Alexander Crane, Audrey Baguette, Djihad Hadjadj, Ashot Harutyunyan, Kiran Kumar, Mirjam Blattner-Johnson, Jayne Vogelzang, Cecilia Sousa, Kyung Shin Kang, Claire Sinai, Dayle Wang, Prasidda Khadka, Hayley Malkin, Patricia Ho, Ryan O'Rourke, Shu Zhang, Rose Gold, Davy Deng, Jonathan Serrano, Matija Snuderl, Chris Jones, Karen Wright, Susan Chi, Jacques Grill, Claudia Kleinman, Liliana Goumnerova, Nada Jabado, David Jones, Mark Kieran, Keith Ligon, Rameen Beroukhim, Pratiti Bandopadhayay
Journal: Neuro-Oncology (2022)

Abstract Pediatric high-grade gliomas (pHGGs), encompassing hemispheric and diffuse midline gliomas (DMGs), remain a devastating disease. The last decade has revealed oncogenic drivers including single nucleotide variants (SNVs) in histones. However, the contribution of structural variants (SVs) to gliomagenesis has not been systematically explored due to limitations in early SV analysis approaches. Using SV algorithms, we recently created, we analyzed SVs in whole-genome sequences of 179 pHGGs including a novel cohort of treatment naïve samples–the largest WGS cohort assembled in adult or pediatric glioma. The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases, including a novel SV amplifying a MYC enhancer in the lncRNA CCDC26 in 12% of DMGs and revealing a more central role for MYC in these cancers than previously known. Applying de novo SV signature discovery, we identified five signatures including three (SVsig1-3) involving primarily simple SVs, and two (SVsig4-5) involving complex, clustered SVs. These SV signatures associated with genetic variants that differed from what was observed for SV signatures in other cancers, suggesting different links to underlying biology. Tumors with simple SV signatures were TP53 wild-type but were enriched with alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A, and RB1 early in tumor evolution, and with extrachromosomal amplicons that likely occurred later. All pHGGs exhibited at least one simple SV signature but complex SV signatures were primarily restricted to subsets of H3.3K27M DMGs and hemispheric pHGGs. Importantly, DMGs with the complex SV signatures SVsig4-5 were associated with shorter overall survival independent of histone type and TP53 status. These data inform the role and impact of SVs in gliomagenesis and mechanisms that shape them.
DDEL-03. The use of programmable valves as a vehicle for intrathecal chemotherapy delivery in infants with CNS tumors and hydrocephalus.
Authors: Rina Dvir, Tom Rosenberg, Ronit Elhasid, Dror Levin, Shlomi Constantini, Jonathan Roth
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Current chemotherapy protocols for treatment of embryonal brain tumors in infants recommend administration of intrathecal chemotherapy either by a lumbar tap or via an Ommaya reservoir. Children with concurrent hydrocephalus and shunts may have sub-therapeutic levels of chemotherapy in the CSF due to constant CSF drainage to extra-CNS compartments. We present our experience in delivery of chemotherapy to young children via programmable valves. RESULTS: A retrospective analysis of infants with CNS malignancies and hydrocephalus treated with a shunt and a programmable valve (CERTAS™ Plus Programmable Valves - Integra Life Sciences) was conducted. Five infants 1.1-3 years of age (mean 2) were included. Pathologies included atypical teratoid rhabdoid tumor (ATRT N=2), medulloblastoma (N=2), and metastatic rhabdomyosarcoma(N=1). Intrathecal injections were conducted in an outpatient setting unless hospitalization was required for other reasons. Only one child required sedation due to noncompliance. A total of 61 chemotherapeutic administrations were performed directly through the valve while set on an extremely high opening pressure for several hours( 35 with hydrocortisone and cytarabine, 26 with topotecan). There were no infections, leaks or major complications. One child required a wound revision due to exposure of the proximal catheter related to extremely thin skin, one child developed somnolence and fever which were not related to a shunt malfunction or infection, and one child had clinical and radiological shunt over-drainage solved by increasing of valve settings. CONCLUSIONS: Programmable ventriculoperitoneal valves appear to a safe method for delivery of chemotherapy in infants with malignant CNS tumors .This technique may potentially have an added value for children with concurrent shunts, and may also obviate the need for an additional ventricular access device .